We have recently identified strong associations between circulating biomarkers of one-carbon metabolism (OCM) and lung cancer within the European Prospective Investigation and Cancer (EPIC) cohort, based on prospectively collected blood samples from 900 cases and 1,800 controls. The study strongly implicated important protective effects for both vitamin B6 and methionine independently of smoking status, resulting in 2.5-fold risk differences between the top and bottom 25% of the population for these vitamin measures combined (p=10-12). Repeat measures indicated that these effects were substantially under-estimated because of regression dilution. The main objectives of this expanded study are two-fold: i) to clarify the role of B-vitamins and related factors (the one-carbon metabolism pathway) in lung cancer etiology in a study population large enough to allow robust risk analyses stratified by smoking status, using both molecular epidemiology and genetic approaches, and ii) to measure the role of OCM biomarkers in lung cancer risk prediction in multiple cohorts. We have initiated a lung cancer consortium in collaboration with over 20 cohorts participating in the NCI Cohort Consortium, including in total 11,500 prospectively collected lung cancer cases with blood samples. This study will include equal proportions of 1,200 never, former, and current smoking case-control pairs recruited in US/European/Australian cohorts, as well as 1,500 case-control pairs recruited in Asian cohorts. We will also include 1,000 repeat samples from a subgroup to allow for correction of regression dilution bias, resulting in biochemical analysis of 11,200 serum/plasma samples. Circulating levels of up to 40 biomarkers of one-carbon metabolism will be measured in the whole study population, and we will quantify their association with subsequent lung cancer risk. Important analyses of a priori interest will include measuring the association with risk among never and former smokers separately. These risk estimates will subsequently be used in risk prediction models, also taking regression dilution into account. Preliminary data from the EPIC cohort indicate that serum measures of methionine and vitamin B6 may identify up to 7-fold differences in life-time risk of lung cancer. Lung cancer remains a major health problem world-wide, and is responsible for 28% of all cancer deaths in the US. As well as elucidating the association between OCM biomarkers and lung cancer, this initiative will create more detailed risk prediction models, over and above that afforded by detailed information on tobacco exposure alone. The important work that will go into the construction of this consortium will also result in opportunities to initiate additional studies concerning lung cancer etiology. PUBLIC HEALTH RELEVANCE: In the US over 225,000 lung cancer cases are diagnosed every year representing approximately 15% of all new cancer cases, and 28% of cancer deaths. Although the main risk factor of lung cancer is tobacco exposure, nearly half of all lung cancer cases in the US occur among former and never smokers. We recently identified strong protective effects of elevated circulating levels of B- vitamins (in particular vitamin B6, folate, and also methionine) in a large cohort including pre-diagnostic blood samples in participants from eight European countries. The proposed study includes equal numbers of never, former and current smokers, aims to clarify a potentially strong beneficial role of B-vitamins and related factors in lung cancer development. The study will be conducted in collaboration with over 20 cohorts, and may identify important biomarkers for lung cancer risk prediction, over and above that afforded information on tobacco exposure.